MicroRNAs (miRNAs) are genome encoded potent negative regulators of gene expression. Binding of miRNA to mRNA within the RNA-induced silencing complex (RISC) leads to either translational inhibition or to slicing of the target mRNA. Recent studies showed that miRNAs play an important role in differentiation of lymphoid cells. However, the role of miRNA in orchestrating lymphocyte differentiation remains largely elusive. We found that deficiency in Ago2, the only Ago protein that possesses mRNA Slicer activity, impairs early B cell development in the bone marrow. This effect of Ago2 deficiency on B cell differentiation points to the existence of the miRNA-dependent developmental check-point mechanism. We hypothesize that this mechanism relies on miRNA dependent and Ago2-mediated cleavage of mRNA encoding negative regulators of B cell differentiation. The achievement of the goals of this project may lead to identification of genes that play a crucial regulatory role in B cell differentiation and B cell immunity in human health and disease. [unreadable] [unreadable] [unreadable]